Force Matters: Biomechanical Regulation of Cell Invasion and Migration in Disease

Fibrotic diseases frequently coincide with stiffened ECMs, and the elevated migration and invasion of resident and exogenous cells. A stiff matrix fosters the formation of actin-rich invadosomes and lamellae. Invadosomes and lamellae are essential subcellular machineries driving cell invasion and migration. Reducing invadosome and lamella formation (and, thus, cellular invasion) through the therapeutic targeting of tissue tension and mechanosignaling could ameliorate disease pathology. Atherosclerosis, cancer, and various chronic fibrotic conditions are characterized by an increase in the migratory behavior of resident cells and the enhanced invasion of assorted exogenous cells across a stiffened extracellular matrix (ECM). This stiffened scaffold aberrantly engages cellular mechanosignaling networks in cells, which promotes the assembly of invadosomes and lamellae for cell invasion and migration. Accordingly, deciphering the conserved molecular mechanisms whereby matrix stiffness fosters invadosome and lamella formation could identify therapeutic targets to treat fibrotic conditions, and reducing ECM stiffness could ameliorate disease progression. Atherosclerosis, cancer, and various chronic fibrotic conditions are characterized by an increase in the migratory behavior of resident cells and the enhanced invasion of assorted exogenous cells across a stiffened extracellular matrix (ECM). This stiffened scaffold aberrantly engages cellular mechanosignaling networks in cells, which promotes the assembly of invadosomes and lamellae for cell invasion and migration. Accordingly, deciphering the conserved molecular mechanisms whereby matrix stiffness fosters invadosome and lamella formation could identify therapeutic targets to treat fibrotic conditions, and reducing ECM stiffness could ameliorate disease progression. a multiprotein complex that nucleates the highly branched F-actin meshwork within lamellipodia. a multiprotein complex surrounding cells within tissue. The ECM provides biochemical and biomechanical cues to cells and modulates cellular behavior. finger-like protrusions comprising parallel actin bundles in their core located at the leading edge of the migrating cells. a macromolecular signaling complex that links the ECM to the intracellular actin cytoskeleton network through the transmembrane protein integrin. cellular protrusion that mediates matrix metalloproteinase-dependent proteolytic degradation of the ECM. actin-rich subcellular compartments, including lamellipodia and filopodia, that are located at the leading cell edge and drive membrane protrusions during cell migration. sheet-like protrusions comprising a highly branched Arp2/3 complex-nucleated actin network at the leading edge of migrating cells. an extracellular enzyme that catalyzes the covalent crosslinking between collagen molecules to stabilize the supramolecular collagen structure. process by which cells sense and translate mechanical cues by converting them into intracellular biochemical signals to control cellular behaviors. a family of membrane-bound or secreted proteolytic enzymes that degrade and remodel ECM proteins. a Rho GTPase-activated effector protein that stimulates Arp2/3-dependent actin polymerization.